Genetic Variant NUBPL:p.Asp105His (chr14-31599310-G-C) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PM5PP3_Strong

The NM_025152.3(NUBPL):c.313G>C(p.Asp105His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D105Y) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

NUBPL
NM_025152.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.92

Publications

9 publications found

Variant links:

Genes affected

NUBPL (HGNC:20278): (NUBP iron-sulfur cluster assembly factor, mitochondrial) This gene encodes a member of the Mrp/NBP35 ATP-binding proteins family. The encoded protein is required for the assembly of the respiratory chain NADH dehydrogenase (complex I), an oligomeric enzymatic complex located in the inner mitochondrial membrane. Mutations in this gene cause mitochondrial complex I deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

NUBPL Gene-Disease associations (from GenCC):

mitochondrial complex I deficiency, nuclear type 21
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen
mitochondrial complex I deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NUBPL links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-31599310-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 50215.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.985

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025152.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NUBPL	NM_025152.3	MANE Select	c.313G>C	p.Asp105His	missense	Exon 4 of 11	NP_079428.2
NUBPL	NM_001201573.2		c.25G>C	p.Asp9His	missense	Exon 2 of 9	NP_001188502.1
NUBPL	NR_120408.2		n.349G>C		non_coding_transcript_exon	Exon 4 of 10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NUBPL	ENST00000281081.12	TSL:1 MANE Select	c.313G>C	p.Asp105His	missense	Exon 4 of 11	ENSP00000281081.7
NUBPL	ENST00000551314.1	TSL:4	c.157G>C	p.Asp53His	missense	Exon 4 of 7	ENSP00000447234.1
NUBPL	ENST00000547839.5	TSL:2	n.313G>C		non_coding_transcript_exon	Exon 4 of 10	ENSP00000449918.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.71

MutationAssessor

Pathogenic

4.3

PhyloP100

6.9

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-6.7

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MutPred

0.93

Loss of catalytic residue at D105 (P = 0.1483)

MVP

0.86

MPC

0.61

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.94

Mutation Taster

=26/74

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over